POS0394 THE CAUSAL RELATIONSHIPS BETWEEN MEMBRANE-ASSOCIATED PROGESTERONE RECEPTOR AND OSTEOPOROSIS: EVIDENCE FROM HUMAN STUDIES
Authors: K. Fan, J. Hu, J. Hou, Q. Yu, P. F. He, X. LI, S. X. Zhang
Journal: Annals of the Rheumatic Diseases (2023)

<h3>Background</h3> The observational association has shown that progesterone is associated with osteoporosis (OP)(1), and progesterone was sometimes used as a therapy in osteoporosis treatment [2]. However, controversy over causality remains unresolved[3]. <h3>Objectives</h3> To reveal the causal association between progesterone and OP. <h3>Methods</h3> We performed two-sample mendelian randomization (MR) analyses. The summary statistics of membrane-associated progesterone receptor were obtained from the INTERVAL study, which characterized the genetic architecture of 1478 human plasma proteins[4]. The genetic associations of femoral neck bone mineral density (FN-BMD, 32735 samples), forearm bone mineral density (FA-BMD, 8143 samples), lumbar spine bone mineral density ((LS-BMD, 28498 samples), and heel bone mineral density (eBMD, 426824 samples) were obtained from GEnetic Factors for OSteoporosis Consortium (GEFOS)(5) and UK Biobank (containing 426,824 individuals)[6]. The significance threshold was set using independent variants in linkage disequilibrium (r<sup>2</sup> &lt; 0.001) at the standard (p &lt; 5e<sup>-6</sup>) to select single nucleotide polymorphisms (SNPs) as instrumental variables. Inverse variance weighted (IVW), weighted median estimator (WME), and MR-Egger regression methods (MR-ER) were performed in mendelian randomization analysis. Sensitivity analyses were then conducted. The MR Pleiotropy Residual Sum and Outlier (MR-PRESSO) were used to detect and correct the outliers in IVW linear regression[7]. <h3>Results</h3> MR analyses found that increased level of membrane-associated progesterone receptor was causally linked to decreased FN-BMD (odds ratio =0.95, 95% confidence interval: 0.92-0.99, P =0.0086). No heterogeneity (Q = 9.77, P <sub>Q</sub> = 0.551) or horizontal pleiotropy (egger regression intercept = -0.008, P = 0.424) was detected. Besides, no significant causation was found between the mineral density of other kinds of bones (FA-BMD, LS-BMD, and eBMD) and progesterone (Figure 1). <h3>Conclusion</h3> This study support that there are detrimental causal effects of progesterone on OP risk. Further randomized controlled trials are needed to clarify the specific protective mechanisms. <h3>References</h3> [1]Recker RR, Davies KM, Dowd RM, Heaney RP. The effect of low-dose continuous estrogen and progesterone therapy with calcium and vitamin D on bone in elderly women. A randomized, controlled trial. Ann Intern Med. 1999;130(11):897-904. [2]Prior JC. Progesterone for the prevention and treatment of osteoporosis in women. Climacteric. 2018;21(4):366-74. [3]Leonetti HB, Longo S, Anasti JN. Transdermal progesterone cream for vasomotor symptoms and postmenopausal bone loss. Obstet Gynecol. 1999;94(2):225-8. [4]Sun BB, Maranville JC, Peters JE, Stacey D, Staley JR, Blackshaw J, et al. Genomic atlas of the human plasma proteome. Nature. 2018;558(7708):73-9. [5]Zheng HF, Forgetta V, Hsu YH, Estrada K, Rosello-Diez A, Leo PJ, et al. Whole-genome sequencing identifies EN1 as a determinant of bone density and fracture. Nature. 2015;526(7571):112-7. [6]Morris JA, Kemp JP, Youlten SE, Laurent L, Logan JG, Chai RC, et al. An atlas of genetic influences on osteoporosis in humans and mice. Nat Genet. 2019;51(2):258-66. [7]Verbanck M, Chen CY, Neale B, Do R. Detection of widespread horizontal pleiotropy in causal relationships inferred from Mendelian randomization between complex traits and diseases. Nat Genet. 2018;50(5):693-8. <h3>Acknowledgements:</h3> NIL. <h3>Disclosure of Interests</h3> None Declared.